Process Involving Cross Metathesis of Olefins

ABSTRACT

A method of forming a macrocyclic musk compound comprising the steps of: —
         i) cross-metathesizing a first olefin and a second olefin in the presence of a homogeneous transition metal catalyst comprising an alkylidene ligand, to form a statistical mixture of a hetero-dimer intermediate of said first and second terminal olefin, and homo-dimers   ii) separating the hetero-dimer from the statistical mixture of hetero- and homo-dimers   iii) and cyclizing the hetero-dimer intermediate to form the macrocyclic musk compound.

The present invention is concerned with a process for the preparation ofmacrocyclic musk compounds utilizing a cross metathesis reaction. Theinvention is also concerned with novel intermediates useful in saidprocess of forming macrocyclic musk compounds.

The odour of musk is perhaps the most universally appreciated fragrance.Synthetic musks can be divided into three major classes aromatic nitromusks, polycyclic musk compounds, and macrocyclic musk compounds. Thedetection of the nitro- and polycyclic chemical groups in human andenvironmental samples initiated a public debate on the use of thesecompounds. Some research has indicated that these musk compounds don'tbreak down in the environment and can accumulate in human bodies. Assuch, macrocyclic musk compounds have increased in importance in recentyears.

Common macrocyclic musk compounds include ambrettolide (9-ambrettolideand 7-ambrettolide), nirvanolide, habanolide, cosmone, muscenone,velvione, civetone and globa none.

7-Ambrettolide naturally occurs in musk ambrette seed oil (M.Kerschbaum, Chem Ber. 1927, 60B, 902) and is a valuable perfume basebecause of its desirable odour. 9-Ambrettolide is likewise a muchappreciated perfumery ingredient (C. Collaud, Helv. Chinn. Acta 1942,25, 965). It is currently synthesized industrially from aleuritic acid.However, aleuritic acid is obtained from shellac by saponfication, anddue to growing industrial concerns regarding the supply and price ofshellac, there is a need to devise new synthetic routes into the highlyvalued and valuable 9-ambrettolide.

Olefin metathesis has become an important tool in the field of syntheticorganic chemistry. A variant of olefin metathesis—so-called crossmetathesis—is the reaction of two different olefins in the presence ofan organometallic catalyst, in which one olefin double bond changesplaces with the other. More particularly, it is an organic reaction thatentails the redistribution of fragments of olefins by the scission andregeneration of carbon-carbon double bonds.

The mechanism of this reaction is thought to proceed via a 2+2cycloaddition of an alkene-bearing substrate to a metal alkylidenecatalyst, forming a metallocyclobutane intermediate, which undergoescycloreversion to generate the substrate loaded with a metal carbene,which further reacts with a second alkene to produce the metathesisproduct and releases the metal alkylidene catalyst.

Schematically, an olefin metathesis reaction can be represented asfollows:

The reaction can be used to couple together two olefin substrates toform a new olefin compound, which is a dimer of the two substrates. Thereaction is shown schematically, above. The A-containing substrate andthe B-containing substrate can react to form a hetero-dimer (shown),however, the both the A-containing substrate and the B-containingsubstrate can react with itself to form homo-dimers.

Another variant of the olefin metathesis reaction is the so-called ringclosure metathesis reaction (RCM). This reaction is widely establishedas a means of forming ring structures. The reverse reaction can beemployed to ring-open a cyclic structure:

RCM is simply an intramolecular olefin metathesis of a diene, yielding acycloalkene and a volatile alkene by-product (ethylene, in the case ofthe above schematic). RCM has been widely researched as a means ofproducing macrocycles. Indeed, a laboratory procedure utilizing a ringclosure metathesis (RCM) reaction using a ruthenium alkylidene catalysthas been reported in the literature (J. Am. Chem. Soc. 2013, 135, 94;Chem. Europ. J. 2013, 19, 2726-2740, J. Org Chem. 1996, 61, 3942-3943,and WO 2012167171). However, a problem with RCM is that theintra-molecular ring closing reaction is in competition withinter-molecular polymerisation reactions, and the former is favouredonly in high dilution, and so for reasons of economy this chemistry hasnot found use industrially as a means of producing macrocyclic muskcompounds to the best of the applicant's knowledge.

In contrast to the greatly researched ring closure metathesis reaction,the cross metathesis reaction has been relatively under studied.Difficulties abound with this chemistry. Catalyst-induced migration ofthe double bonds on the starting materials represents a consistentchallenge. Furthermore, differences in reactivity of the olefin groupsof the starting materials can lead to poor yields of the desiredproduct. Still further, the inevitable complex mixture containinghomo-dimers and hetero-dimers can be difficult, time consuming andexpensive to separate and isolate in pure form, particularly when thereaction and purification must be industrially scalable.

The present invention addresses the problems in the prior art andprovides an efficient and high-yielding synthesis of macrocyclic muskcompounds and their open-chain intermediates, utilizing crossmetathesis.

Accordingly, the invention provides in a first aspect a method offorming a macrocyclic musk compound comprising the steps of crossmetathesizing a first olefin and a second olefin in the presence of ahomogeneous transition metal catalyst containing an alkylidene ligand,to form a hetero-dimer intermediate of said first and second olefin, andcyclizing the hetero-dimer intermediate to form the macrocyclic muskcompound.

In a particular embodiment of the present invention, one or both offirst and second olefins may be olefins with a terminal double bond.

In a particular embodiment of the invention, the first step in thepreparation of the macrocyclic musk compound, wherein the first andsecond olefins are reacted in a cross metathesis reaction to produce thehetero-dimer intermediate is shown schematically below.

The group R contains a protected hydroxyl group containing 3 to 10carbon atoms; R₁ is a carboxylic ester group containing 3 to 11 carbonatoms; wherein the number of carbon atoms in the ester group andprotected hydroxyl group together should be less than 15; and whereinM=represents a transition metal catalyst containing an alkylideneligand.

One of said first or second olefins may be represented by the formula(I)

wherein OR₂ is a protected hydroxyl group, which may be selected from analkyl ether group; an ester group; a silyl ether group; or a carbonategroup; R₃ is H or methyl; and n is an integer from 1-8.

Suitable ether protecting groups include a branched or non-branchedalkyl moiety containing 1 to 5 carbon atoms, for example methyl, ethyl,propyl, i-propyl, t-Bu or t-amyl.

Suitable ester protecting groups include C(O)R₄, wherein R₄=hydrogen, ora branched or non-branched alkyl moiety containing 1 to 7 carbon atoms,for example methyl, ethyl, propyl, i-propyl, t-butyl or t-amyl. Suitablesilyl ether protecting groups include Si(R₅)₃; wherein R₅ is a branchedor unbranched alkyl moiety, which may include methyl, ethyl and propyland t-butyl.

Suitable carbonate protecting groups include C(O)OR₆, wherein R₆ is abranched or non-branched alkyl moiety, for example methyl, ethyl orpropyl.

The other of said first or second olefins may be represented by theformula (II)

wherein R₇ is branched or non-branched alkyl moiety containing 1 to 5carbon atoms, and preferably methyl or ethyl, and m is an integer from 1to 10, preferably 7.

When first and second olefins specifically referred to above in formula(I) and (II) are subjected to a cross metathesis reaction in accordancewith the present invention, the hetero-dimer intermediate can berepresented by the formula (III)

wherein R₂, R₇, m and n are as hereinabove defined, and wherein theconfiguration of the double bond may be E or Z as desired.

The hetero-dimer intermediates herein defined, as well as theirpreparation by cross metathesis each represent further aspects of thepresent invention.

In a particular embodiment of the present invention, the hetero-dimerintermediate is a compound represented by the formula (IV)

wherein R₇ is as hereinabove defined, in particular methyl.

The advantages of the t-Bu ether protecting group are manifold, and leadto an over-all efficiency of the synthesis of macrocyclic musks. Inparticular, the t-Bu protecting group is advantageous because it resultsin a hetero-dimer product that can be relatively easily separated fromhomo-dimer side products formed in the cross metathesis reaction bydistillation at relatively low temperatures, e.g. below about 100 to 220degrees centigrade at a pressure of about 1 to 10 mbar. Furthermore,this hetero-dimer is relatively easy to cleave under mild conditionsduring the subsequent macrocyclization step to form the macrocyclicmusk.

After completion of the metathesis reaction, the hydroxyl protectinggroup can be cleaved by various synthetic procedures depending on thenature of the protecting group, all of which are well known to a personskilled in the art. The resultant α-ω hydroxy ester can be cyclised toform a macrocyclic lactone. In the particular case of a α-ω hydroxyesters represented in protected form (IV) above, the correspondingmacrocyclic musk compound is the lactone E/Z 9-ambrettolide (structureshown below).

When the protecting group is an ester, the hetero-dimer formed by themetathesis reaction can be immediately submitted to the macrocyclizationreaction without prior cleavage of the protecting group. Examples of thesynthetic steps do not need to be exhaustively explained here, and aremore specifically described in the examples, below.

Thereafter, the macrocyclization reaction may be carried out accordingto techniques known in the art. A particular method of carrying out thecyclization step proceeds via the formation of a polyester from ahydroxy ester, which is the unprotected hetero-dimer of the metathesisreaction, and continuously trans-esterifying the polyester into volatilelactones and removing them at higher temperature and reduced pressureonce the lactone is formed according to the well-known Collaud chemistrydisclosed U.S. Pat. No. 2,234,551, which is herein incorporated byreference. Further details regarding this chemistry are set forth in theexamples hereinbelow.

Whereas a hetero-dimer intermediate described above can be cyclized toform 9-ambrettolide, the skilled person will appreciate that with theappropriate selection of olefin starting materials, in particularunsaturated protected alcohol and unsaturated carboxylic acid ester, thecross metathesis reaction will form hetero-dimers that can besubsequently transformed by macrocyclization to form other macrocyclicmusk compounds such as 7-Ambrettolide

or Habanolide

or Nirvanolide

For example, the first and second olefin compounds that can be used toform 7-ambrettolide may be selected from 10-(tert-butoxy)dec-1-ene andmethyl oct-7-enoate or dec-9-en-1-yl acetate and methyl oct-7-enoate.

The first and second olefin compounds that can be used to formHabanolide may be selected from trimethyl(pent-4-en-1-yloxy)silane andethyl dodec-11-enoate.

The first and second olefin compounds that can be used to formNirvanolide may be selected from from 4-methyl-6-(tert-butoxy)hex-1-eneand methyl 9-decenoate, or 4-methyl-6-(tert-butoxy)hex-1-ene and ethyl9-decenoate, or 3-methylhex-5-en-1-yl propionate and methyl 9-decenoate.

The cross metathesis reaction conditions required to conjoin the twoolefins are generally well known in the art. The reaction may proceed atroom temperature or at elevated or lowered temperatures, for examplebetween 0 to 60 degrees centigrade.

Whereas in ring closure metathesis reactions to form macrocycles, it isnecessary to carry out the reaction in very high dilutions (for example,10⁻² to 10⁻⁴ M solutions), in contrast applicant has found that in thepresent invention the cross metathesis reaction will proceed at highconcentrations, and indeed the reaction may even be carried out with nosolvent present. As such, the method of the present invention, whereby ahetero-dimer is first formed by metathesis, and then ring-closed by amacrocyclization step, represents a considerably simpler and cheaperprocess than RCM to form nnacrocyclic musk compounds, which isindustrially scalable in an economic manner.

Elimination of solvent from a reaction mixture has very obvious economicadvantages for the industrialization of a synthetic procedure. Anadditional advantage related to the reduction or avoidance of a solvent,particularly in relation to the use of metathesis catalysts that may bewater and oxygen sensitive, is that there is one less reagent that needsto be conditioned or purified before use to eliminate trace contaminantssuch as moisture and reactive oxygen, such as in the form of peroxides.

In a particular aspect of the present invention, feed stock containingfirst or second olefin compounds can be subjected to a purification stepprior to their reaction by cross metathesis. Purification entails theremoval of contaminants from said feed stocks containing the olefincompounds that could otherwise negatively affect the reactivity ofmetathesis catalysts. Such contaminants may include water, alcohols,aldehydes, peroxides, hydroperoxides, protic materials, polar materials,Lewis base (basic) catalyst poisons and two or more thereof.Purification may entail a physical purification step, for example, adistillation step, or a step whereby the olefin compounds are separatedfrom unwanted contaminants by a process of absorption. Physicalpurification means may include heat (such as, in a distillationprocess), or contact of the feed stocks with absorbent materialsselected from molecular sieves, alumina, silica gel, montmorilloniteclay, Fuller's earth, bleaching clay, diatomaceous earth, zeolites,kaolin, activated metals, metal sulfates, metal halides, metalsilicates, activated carbon, and soda ash.

Additionally or alternatively, purification may entail a chemicalpurification step, whereby unwanted contaminants are separated from thefeed stocks by subjecting the contaminants to a chemical reaction,whereby they are converted to materials that are non-reactive with ametathesis catalyst. Chemical purification means include treating thefeed stocks with metal carbonates and metal hydrogen carbonates, acidanhydrides, metal hydrides, phosphorous pentoxide, metal aluminumhydrides, alkyl aluminum hydrides, trialkyl aluminums, metalborohydrides, organometallic reagents, metal amides, and combinationsthereof. Contaminants may be compounds that contain at least one protonthat can react with a compound selected from the group consisting ofmetal carbonates and metal hydrogen carbonates, acid anhydrides, metalhydrides, phosphorous pentoxide, metal aluminum hydrides, alkyl aluminumhydrides, trialkyl aluminums, metal borohydrides, organometallicreagents, metal amides, and combinations thereof.

Purification may also be performed by contacting feed stock withmaterials selected from the group consisting of molecular sieves,activated alumina, activated acidic alumina, neutral alumina, any one ofwhich may be optionally heat treated; and activated basic alumina,alkaline earth metal hydrides, alkaline earth metal sulfates, alkalimetal sulfates, alkali earth metal halides, alkali metal aluminumhydrides, alkali metal borohydrides, Grignard reagents; organolithiumreagents, trialkyl aluminums, metal bis(trimethylsilyl)amides, andcombinations thereof.

Purification may also be performed by contacting feed stock with CaH₂,activated Cu, activated Mg, acetic anhydride, calcium sulfate, magnesiumsulfate, potassium sulfate, aluminum sulfate, potassium magnesiumsulfate, sodium sulfate, calcium carbonate, sodium carbonate, magnesiumsilicate, potassium chloride, LiAlH₄, NaAlH₄, iBu₂AlH, n-butyl lithium,t-butyl lithium, sec-butyl lithium, triethyl aluminum, tributylaluminum, triisopropyl aluminum, trioctyl aluminum, lithium diisopropylamide, KHMDS, and combinations thereof.

Purification may also be carried out by subjecting feed stock to ananhydride of an organic acid. Suitable anhydrides are preferably theanhydrides of aliphatic, cyclic, alicyclic organic acids having from 1to 10 carbon atoms, or an aromatic organic acid having from 6 to 10carbon atoms. Such compounds are known in the art or may be producedaccording to known methods. A particularly useful organic anhydride isacetic anhydride.

Purification may also be carried out by subjecting feed stock to anorganometallic compound of aluminum. Said organometallic compound ofaluminum may be a tri-substituted aluminium compound wherein thesubstituents are independently selected from an aliphatic, cyclic,alicyclic residue having from 1 to 10 carbon atoms, or from aromaticresidues having from 6 to 10 carbon atoms. Such compounds are known inthe art or may be produced according to known methods.

In one embodiment, the organometallic compound of aluminum is triethylaluminum, tributyl aluminum, triisobutyl aluminum, triisopropylaluminum, or trioctyl aluminum.

Trioctyl aluminum is particularly preferred since it is stable incontact with air, i.e. is not-flammable in contact with air, which isnot the case with triethyl aluminum. This renders it particularlysuitable for applications at an industrial scale.

For the practical realization of a chemical purification step, theamount of contaminant may be determined by known methods, such aschromatographic methods. Thereafter, the theoretical amount ofpurification means needed to react with the contaminant and render itinactive to a catalyst can be easily calculated, and can be employed inslight molar excess in order to ensure that all potentially harmfulcontaminant is reacted to render it inactive towards a catalyst. Ifdesired, after the reaction with contaminant, any excess purificationmeans can be removed.

After purification, feedstock containing first and/or second olefincompounds useful in the present invention may have a level of puritythat is at least 99.9% by weight of the first and/or the second olefin,or at least 99.99% by weight, or at least 99.999% by weight.

Several different and complementary means of purification of acontaminated feedstock comprising said first and/or said second olefincompounds can be carried out prior to a metathesis reaction according tothe invention. The following non-exhaustive and non-limiting list ofrepresentative purification methodologies can be usefully employed, forexample (a) thermal treatmentfor example, heating (and/or distilling) afeed stock at a temperature of between about 100° C. and about 250° C.,depending on the boiling point of a feed stock, optionally with a purgeof an inert gas or under vacuum, and/or treatment with an adsorbentmaterial referred to hereinabove can be useful both in decomposingperoxide contaminants and/or decomposition products thereof or adsorbingcontaminants; (b) treatment with an acid anhydride (e.g., aceticanhydride, Ac₂O) can be useful in removing moisture, activehydroxyl-containing materials (e.g., alcohols), and hydroperoxides (viaacetylation); (c) treatment with a desiccant (e.g., silica gel, alumina,molecular sieves, magnesium sulfate, calcium sulfate, and the like, andcombinations thereof) and/or an organometallic reagent (e.g., t-butyllithium, triethyl aluminum, tributyl aluminum, triisobutyl aluminum,triisopropyl aluminum, trioctyl aluminum, and the like, and combinationsthereof) and/or metal hydrides (e.g., CaH₂ and the like) and/or acidanhydrides (e.g., acetic anhydride and the like) can be useful inremoving moisture; (d) treatment with an adsorbent (e.g., alumina,silica gel, and the like, and combinations thereof) and/or anorganometallic reagent (e.g., t-butyl lithium, triethyl aluminum,tributyl aluminum, triisobutyl aluminum, triisopropyl aluminum, trioctylaluminum, and the like, and combinations thereof) and/or a metal amide(e.g., LDA, KHMDA, and the like) can be useful in removing proticmaterials; (e) treatment with an adsorbent (e.g., alumina, silica gel,activated charcoal, and the like, and combinations thereof) can beuseful in removing polar materials; and (f) treatment with anorganometallic reagent (e.g., t-butyl lithium, triethyl aluminum,tributyl aluminum, triisobutyl aluminum, triisopropyl aluminum, trioctylaluminum, and the like, and combinations thereof) can be useful inremoving Lewis basic catalyst poisons or the like.

In some embodiments, the means used to purify said feedstock prior to ametathesis reaction comprises an adsorbent which, may be selected fromthe group consisting of silica gel, alumina, bleaching clay, activatedcarbon, molecular sieves, zeolites, Fuller's earth, diatomaceous earth,and the like, and combinations thereof. In some embodiments, the meansis selected from the group consisting of optionally heat-treatedmolecular sieves, optionally heat-treated alumina, and a combinationthereof. In some embodiments, the adsorbent comprises optionallyheat-treated activated alumina which, may be selected from the groupconsisting of optionally heat-treated activated acidic alumina,optionally heat-treated activated neutral alumina, optionallyheat-treated activated basic alumina, and combinations thereof. In someembodiments, the absorbent comprises optionally heat-treated activatedneutral alumina, which can be useful in treating substrates (e.g.,olefins) that are susceptible to acid-catalyzed isomerization and/orrearrangement.

For embodiments in which the means for purification comprises anadsorbent (e.g., molecular sieves, alumina, etc.), it is presentlybelieved that the treating of the feedstock with the adsorbent is moreeffectively performed by flowing the feedstock through the means forpurification using a percolation- or flow-type system (e.g.,chromatography column) as opposed to simply adding the adsorbent to thesubstrate in a container. In some embodiments, about 20 wt % of aluminais used in a column. In particular, it may be particularly advantageousto treat a feedstock with alumina on about a 5-to-1 weight-to-weightbasis. However, it is to be understood that the amount of alumina usedis not restricted and will be both feedstock- and impurity dependent inaddition to being impacted by the form of the alumina, its activationprocess, and the precise treatment method (e.g., flow through a columnvs. direct addition to container). In some embodiments, the means usedfor purifying the feedstock prior to a metathesis reaction comprises atrialkyl aluminum which, in some embodiments, is selected from the groupconsisting of triethyl aluminum, tributyl aluminum, triisobutylaluminum, triisopropyl aluminum, trioctyl aluminum, and the like, andcombinations thereof.

It has further been unexpectedly found that the purification period ofthe feed stock may significantly influence efficacy of the chemicalpurification step. Accordingly, prolonged purification periods mayimprove catalytic activity of the compounds used as catalysts in themetathesis reactions according to the invention.

In one embodiment, preferably when a trialkyl aluminum compound is usedfor purification, preferably trioctyl aluminum, the feedstock issubjected to said compound for a period of from 2 to 100 h, preferably 5to 90 h, more preferred 10 to 80 h, and still more preferred 15 to 70 h.

Catalysts for effecting metathesis reactions are well known in the art.Generally, olefin metathesis catalysts are organometallic catalystsbearing a transition metal atom, such as titanium (Ti), tantalum (Ta),ruthenium (Ru), molybdenum (Mo) or tungsten (W). Whilst varyingconsiderably in terms of the ligands bound to the metal atom, all of theeffective catalyst systems share the basic metal alkylidene oralkylidyne ligand structure. Reviews of metathesis catalysts useful inthe present invention are described in Michrowska et al Pure Appl.Chem., vol 80, No. 1, pp 31-43 2008; Schrock et al Chem. Rev. 2009, 109,3211-3226; and Grubbs et al J. Am. Chem. Soc. 2011, 133, 7490-7496.Suitable catalysts are also described in the patent literature, forexample in US 2013/0281706 and U.S. Pat. No. 6,306,988.

The variety of substituents or ligands that can be employed in thecatalysts means that there are, today, a wide variety of catalystsavailable. Ligands or substituents may be selected to affect catalyststability or selectivity (chemo-, regio- and enantio-selectivity), aswell as turn over number (TON), and turn over frequency (TOF). As iswell known in the art, the TON describes the degree of activity of acatalyst, i.e. the average number of substrate molecules converted permolecule of catalyst, whereas TOF is a representation of catalystefficiency (in units h⁻¹).

Particularly useful catalysts in the metathesis reaction of the presentinvention are those metal alkylidene catalysts wherein the metal atom iseither a Ruthenium, Molybdenum or Tungsten atom. Most preferred are saidcatalysts wherein the metal atom is Molybdenum or Tungsten.

Preferred Molybdenum or Tungsten catalysts are represented by thegeneral formula

whereinM=Mo or W; R¹ is aryl, heteroaryl, alkyl, or heteroalkyl; optionallysubstituted; R² and R³ can be the same or different and are hydrogen,alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, or heteroaryl; whichare optionally substituted;

R⁵ is alkyl, alkoxy, heteroalkyl, aryl, aryloxy, heteroaryl, silylalkyl,silyloxy, optionally substituted; and R⁴ is a residue R⁶—X—, wherein

X═O and R⁶ is aryl, which are optionally substituted; or

X═S and R⁶ is aryl, which are optionally substituted; or

X═O and R⁶ is (R⁷, R⁸, R⁹)Si; wherein R⁷, R⁸, R⁹ are alkyl or phenyl,which are optionally substituted; or

X═O and R⁶ is (R¹⁰, R¹¹, R¹²)C, wherein R¹⁰, R¹¹, R¹² are independentlyselected from phenyl, alkyl; which are optionally substituted;

or R⁴ and R⁵ are linked together and are bound to M via oxygen,respectively

Particularly preferred metathesis catalysts are set forth below.

The selection of the catalyst may have significant effects on both theefficiency of the metathesis reaction, characterized by the catalystloading in ppm, as well as on the diastereoselectivity, i.e. the E/Zratio of the double bond in the macrocyclic ring. For instance,catalysts X052, X061, X123 and X190 are preferred catalysts for thesynthesis of E9-Ambrettolide. These catalysts generally generate highE-selectivities and high conversions. Catalysts X039 and X054, which arecharacterized by particularly large phenolic ligands, are capable ofproducing high Z-selectivities in the cross metathesis reaction and arethe preferred catalysts for the synthesis of Nirvanolide. The selectionof optimized conditions of the cross-metathesis reaction depends on thenature of the individual substrate, the catalyst and its loadings aswell as the degree of purification of substrates and solvents (if used),as further described in detail below.

The olefins used as substrates in the metathesis reaction of the presentinvention may be employed in a molar ratio of 1:X, wherein X is 1 orgreater, and may be an integer or a number having a fractional part.More particularly, X is an integer or a number having a fractional part,between 1 and 10.

Assuming full conversion, statistically, a 1:1 mixture of olefinsubstrates will result in a maximum yield of 50% of the desiredhetero-dimer product and 25% each of two homo-dimer products. Whereas,at first sight this appears to represent only a moderate yield of thedesired hetero-dimer product, it represents a thermodynamic mixture andis the highest yield of hetero-dimer that can be achieved. If X is aninteger or a number having a fractional part, which is greater than 1,then a mixture of hetero-dimer to first and second homo-dimers will beobtained in a molar ratio of 2X:1:X².

Employing a ratio of 1:X, wherein X is a relatively large number wouldmake economic sense if the first homo-dimer (the minor reaction productin the mixture) was a dimer of relatively expensive olefin startingmaterial, and the second homo-dimer (the overwhelmingly major product inthe reaction mixture) was the homo-dimer of a relatively inexpensiveolefin starting material, or was otherwise an industrially usefulby-product in its own right, or was easily and cheaply separable fromthe other ingredients of the mixture, for example, byre-crystallization.

Irrespective of the molar ratio of olefin starting materials that isemployed in the present invention, the result of the metathesis reactionis a complex mixture. In order for such a reaction to be industriallyscalable, it should be possible to separate the desired hetero-dimerfrom the homo-dimers in a cheap and efficient manner. Applicant hassurprisingly found that the judicious selection of the protecting groupfor the hydroxyl group on the olefin starting material of formula (I)above can influence the down-stream purification of the hetero-dimer.More particularly, when the protecting group is an alkyl ether, and moreparticularly the iso-propyl or t-butyl ether, not only is there is clearseparation of the boiling points of the hetero-dimer and thehomo-dimers, but all of the dimers in the reaction mixture boil atrelatively low temperatures, such that distillation can be employed atrelatively low temperatures, e.g. about 100 to 220 degrees centigrade,at easily attainable reduced pressure of about 1 to 10 mbar.Furthermore, the t-butyl protecting group is easily cleavable, whichprovides that the subsequent macrocyclization step to form themacrocyclic musk can be carried out under relatively mild reactionconditions.

Accordingly, in another aspect of the present invention, the mixture ofthe hetero-dimer and homo-dimers formed by the cross-metathesis reactionmay be separated by distillation, wherein the distillation temperatureis between 100 to 220 degrees centigrade at a pressure of between 1 to10 mbar.

In a particular embodiment of the present invention, in the method ofseparating the mixture of hetero-dimer from the homo-dimers, the mixtureis formed from a first and second olefin employed in a 1:1 molar ratio.

In a particular embodiment of the present invention, in a method ofseparating the mixture of hetero-dimer from the homo-dimers, theprotecting group on the hetero-dimer is an alkyl ether, and moreparticularly a t-butyl ether.

In order for a process to be industrially scalable, not only must it bepossible to easily and cheaply separate the hetero-dimer from thehomo-dimers, it should also be possible to recycle the homo-dimerby-products. The homo-dimer by-products can be treated with ethylene anda metathesis catalyst to regenerate the first and second olefin startingmaterials in a straightforward manner and conventional manner.

Accordingly, in another aspect of the present invention, the homo-dimersformed in a cross-metathesis reaction described herein, are separatedfrom the hetero-dimer, and are treated with ethylene to regenerate firstand second olefins.

The ethylenolysis treatment of the homo-dimers can be carried out underan appropriate pressure of ethylene gas. An appropriate pressure ofethylene would be between 1 bar and 20 bar. The reaction may be carriedout at a temperature of between 10° C. and 50° C.

Whereas ethylenolysis is an efficient way to re-cycle the homo-dimers,nevertheless, one has to work under a high pressure of ethylene, whichadds complexity and cost to the process.

Surprisingly, applicant has found that rather than subjecting thehomo-dimers to ethylenolysis to regenerate the first and second olefins,the homo-dimers can be directly re-cycled by adding to them an amount ofmetathesis catalyst and subjecting them to a metathesis reaction.

In this re-cycling step, the homo-dimers may be mixed together as thesole reactants in a cross-metathesis reaction; or they may singularly,or in combination, be admixed with one or both of first and secondolefins, before subjecting this mixture in a cross-metathesis reaction.Different recycling scenarios are schematically presented below. Forexample, the homo-dimers can be re-cycled alone, as set out in Scenario1 below, or they can be re-cycled in admixture with first and secondolefins (Scenario 2); or one homo-dimer can be reacted with thecomplementary olefin (Scenario 3 or 4).

The skilled person will appreciate that the homo-dimers can be mixed,optionally with the first and second olefins, to form a a statisticalmixture in which the desired hetero-dimer 16ai is again formed with 50%yield. In this way, after a second metathesis step the hetero-dimer canbe converted with 75% yield.

Accordingly, in another aspect of the present invention, thecross-metathesis reaction comprises a cross-metathesis step of first andsecond olefins defined hereinabove, and a subsequent cross-metathesisstep of homo-dimers formed from the preceding cross-metathesis step.

The skilled person will appreciate that the recycling of homo-dimers isnot limited to single recycling step. Subsequent recycling steps can becarried out, all of which can achieve a statistical mixture containingthe desired hetero-dimer with 50% yield. Of course, the absolute amountof hetero-dimer recovered after each recycling step diminishes and sothe number of recycling steps one performs is determined by thediminishing economic returns.

The fact that homo-dimers could be re-cycled in this way was surprising.The homo-dimers contain internal double bonds and as such would beexpected to react very slowly, if at all, and it was not predictablethat a statistical mixture containing the desired hetero-dimer would beformed, at least in a reasonable time that would make sense in thecontext of an industrial process. However, applicant found that thehomo-dimers displayed substantially similar reaction kinetics as thefirst and second olefins, even when the first and second olefinscontained terminal double bonds.

The synthetic methods described herein are particularly atom efficient,and as such represent a very efficient means of producing macrocyclicmusk compounds on an industrial scale.

In particular, the use of terminal olefins as starting materials meansthat ethylene is eliminated as a by-product of the metathesis reaction.Only two carbon atoms are lost in this case, and if desired, thegenerated ethylene can be recovered and used in any subsequentethyleneolysis reaction that is carried out on the homo-dimers.

However, notwithstanding the advantages attendant to the use of terminalolefins, applicant found that there are drawbacks associated with theiruse. In particular, the elimination of ethylene as a by-product canreduce the efficiency of the metathesis catalysts. Without wishing to bebound by any particular theory, it is possible that ethylene coulddeactivate the catalysts to a certain extent. Still further, certainmetathesis catalysts, and in particular the ruthenium-based catalysts,can cause the terminal double bond of each of the starting materials tomigrate, and also cause isomerization on the double bond in thehetero-dimer.

Surprisingly, however, applicant found that when using molybdenum andtungsten metathesis catalysts, and particularly those preferredmolybdenum and tungsten catalysts referred to specifically hereinabove,there was substantially no double bond migration. Furthermore, there wasrelatively little isomerization about the double bond of thehetero-dimer. For example, with regard to the molecule 9-Ambrettolide,it was possible to obtain the molecule with high E-specificity. Moreparticularly, it was possible to obtain E/Z 9-Ambrettolide in a ratio ofabout 80:20 to 90:10, more particularly about 85:15.

There now follows a series of examples, which serves to illustrate theinvention.

Synthesis of Olefin Substrates:

Oct-7-en-1-yl 2,2-dimethylpropanoate (3a)

oct-7-en-1-ol (1) (50.00 g, 390 mmol) and triethylamine (43.4 g, 429mmol, 59.8 mL, 1.1 equiv.) were dissolved in dry dichloromethane (500mL) and 1.1 equivalent of pivaloyl chloride (2) (51.7 g, 429 mmol, 52.80mL) was added dropwise to the reaction mixture and it was stirred at rtovernight. After the reaction had been completed, it was washed withwater (3×100 mL) and brine (2×100 mL), dried over magnesium sulphate andevaporated. The crude product was purified by distillation (80-82° C./5Hg mm) to yield 24.26 g (29.30%) ester (3a) as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 1.19 (s, 9H), 1.28-1.42 (m, 6H), 1.54-1.68(m, 2H), 2.04 (q, J=7.0 Hz, 2H), 4.04 (t, J=7.0 Hz, 2H), 4.90-5.06 (m,2H), 5.68-5.90 (m, 1H). GC-MS: 96.2% MS (EI): 212.

Oct-7-en-1-yl pentanoate (3b)

2.0 equivalents of thionyl chloride (23.29 g, 195.8 mmol, 14.22 mL) wereadded to a solution of valeric acid (4) (10.00 g, 97.9 mmol) in drydichloromethane (100 mL) and the reaction mixture was stirred at rt for6 h. After completion of the reaction, it was concentrated, then theresidue was dissolved in dry dichloromethane (100 mL), cooled to 5-10°C. and 1.3 equivalent of oct-7-en-1-ol (1) (16.32 g, 127 mmol) was addedto the reaction mixture in one portion followed by dropwise addition oftriethylamine (12.88 g, 127 mmol, 17.74 mL, 1.3 equiv.) and stirred atrt for 3 h. After the reaction had been completed, it was washed withwater (3×50 mL) and brine (2×50 mL), dried over magnesium sulphate andevaporated. The crude product was purified by distillation (94-97° C./7Hg mm) to yield 13.20 g (63.50%) ester (3b) as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 0.91 (t, J=7.0 Hz, 3H), 1.24-1.46 (m, 8H),1.54-1.70 (m, 4H), 2.04 (q, J=7.0 Hz, 2H), 2.29 (t, J=7.0 Hz, 2H), 4.05(t, J=7.0 Hz, 2H), 4.88-5.06 (m, 2H), 5.69-5.91 (m, 1H). GC-MS: 96.4% MS(EI): 212.

Oct-7-en-1-yl hexanoate (3c)

2.0 equivalents of thionyl chloride (20.49 g, 172.2 mmol, 12.51 mL) wereadded to a solution of hexanoic acid (5) (10.00 g, 86.1 mmol) in drydichloromethane (100 mL) and the reaction mixture was stirred at rt for6 h. After completion of the reaction, it was concentrated, then theresidue was dissolved in dry dichloromethane (100 mL) cooled to 5-10° C.and 1.3 equivalent of oct-7-en-1-ol (1) (14.35 g, 112 mmol) was added tothe reaction mixture in one portion followed by dropwise addition oftriethylamine (11.33 g, 112 mmol, 15.60 mL, 1.3 equiv.) and stirred atrt for 3 h. After the reaction was completed, it was washed with water(3×50 mL) and brine (2×50 mL), dried over magnesium sulphate andevaporated. The crude product was purified by distillation (96-98° C./7Hg mm) to yield 14.15 g (72.6%) ester (3c) as a colorless liquid. ¹H-NMR(200 MHz, CDCl₃): δ 0.89 (t, J=7.0 Hz, 3H), 1.21-1.45 (m, 10H),1.54-1.70 (m, 4H), 2.04 (q, J=7.0 Hz, 2H), 2.28 (t, J=7.0 Hz, 2H), 4.05(t, J=7.0 Hz, 2H), 4.88-5.04 (m, 2H), 5.68-5.90 (m, 1H). GC-MS: 95.8% MS(EI): 226.

Oct-7-en-1-yl heptanoate (3d)

2.0 equivalents of thionyl chloride (18.27 g, 153.6 mmol, 11.12 mL) wereadded to a solution of heptanoic acid (6) (10.00 g, 76.8 mmol) in drydichloromethane (100 mL) and the reaction mixture was stirred at rt for6 h. After completion of the reaction, it was concentrated, then theresidue was dissolved in dry dichloromethane (100 mL) cooled to 5-10° C.and 1.3 equivalent of oct-7-en-1-ol (1) (12.80 g, 99.8 mmol) was addedto the reaction mixture in one portion followed by dropwise addition oftriethylamine (10.10 g, 99.8 mmol, 13.92 mL, 1.3 equiv.) and stirred atrt for 3 h. After the reaction had been completed, it was washed withwater (3×50 mL) and brine (2×50 mL), dried over magnesium sulphate andevaporated. The crude product was purified by distillation (97-99° C./7Hg mm) to yield 13.56 g (73.40%) ester (3d) as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 0.88 (t, J=7.0 Hz, 3H), 1.20-1.41 (m, 12H),1.54-1.70 (m, 4H), 2.04 (q, J=7.0 Hz, 2H), 2.28 (t, J=7.0 Hz, 2H), 4.05(t, J=7.0 Hz, 2H), 4.88-5.06 (m, 2H), 5.68-5.90 (m, 1H). GC-MS: 95.2% MS(EI): 240.

Oct-7-en-1-yl decanoate (3e)

2.0 equivalents of thionyl chloride (20.73 g, 174.2 mmol, 12.65 mL) wereadded to a solution of decanoic acid (7) (15.00 g, 87.1 mmol) in drydichloromethane (150 mL) and the reaction mixture was stirred at rt for6 h. After completion of the reaction, it was concentrated then theresidue was dissolved in dry dichloromethane (150 mL) cooled to 5-10° C.and 1.3 equivalent of oct-7-en-1-ol (1) (14.52 g, 113 mmol) was added tothe reaction mixture in one portion followed by dropwise addition oftriethylamine (11.46 g, 113 mmol, 15.78 mL, 1.3 equiv.) and stirred atrt for 3 h. After the reaction had been completed, it was washed withwater (3×70 mL) and brine (2×70 mL) dried over magnesium sulphate andevaporated. The crude product was purified by distillation (146-148°C./5 Hg mm) to yield 16.85 g (68.50%) ester (3e) as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 0.87 (t, J=7.0 Hz, 3H), 1.16-1.46 (m, 18H),1.52-1.72 (m, 4H), 1.92-2.10 (m, 2H), 2.28 (t, J=7.0 Hz, 2H), 4.05 (t,J=7.0 Hz, 2H), 4.88-5.08 (m, 2H), 5.68-5.90 (m, 1H). GC-MS: 95.6% MS(EI): 282.

Trimethyl(oct-7-en-1-yloxy)silane (3f)

A solution of chlorotrimethylsilane (8) (50.84 g, 468 mmol, 1.2 equiv.)in dry dichloromethane (150 mL) was added to a solution of oct-7-en-1-ol(1) (50.00 g, 390 mmol) and imidazole (31.86 g, 468 mmol) in drydichloromethane (350 mL) and the reaction mixture was stirred at 40° C.overnight. After the reaction had been completed, it was washed withwater (3×100 mL) and brine (2×100 mL), dried over magnesium sulphate andevaporated. The crude product was purified by distillation (76-80° C./5Hg mm) to yield 64.22 g (82.20%) silyl ether (3f) as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 0.10 (s, 9H), 1.24-1.60 (m, 8H), 2.04 (q,J=7.0 Hz, 2H), 3.56 (t, J=7.0 Hz, 2H), 4.88-5.06 (m, 2H), 5.70-5.92 (m,1H). GC-MS: >99.0% MS (EI): 200.

tert-Butyldimethyl(oct-7-en-1-yloxy)silane (3g)

A solution of tert-butylchlorodimethylsilane (9) (64.70 g, 429 mmol, 1.1equiv.) in dry dichloromethane (150 mL) was added to a solution ofoct-7-en-1-ol (1) (50.00 g, 390 mmol) and imidazole (31.90 g, 468 mmol,1.2 equiv.) in dry dichloromethane (350 mL) and the reaction mixture wasstirred at rt overnight. After the reaction had been completed, it waswashed with water (3×100 mL) and brine (2×100 mL), dried over magnesiumsulphate and evaporated. The crude product was purified by distillation(85-90° C./5 Hg mm) to yield 52.20 g (55.20%) silyl ether (3g) as acolorless liquid. ¹H-NMR (200 MHz, CDCl₃): δ 0.05 (s, 6H), 0.89 (s, 9H),1.28-1.42 (m, 6H), 1.42-1.58 (m, 2H), 2.04 (q, J=7.0 Hz, 2H), 3.60 (t,J=7.0 Hz, 2H), 4.90-5.06 (m, 2H), 5.70-5.90 (m, 1H). GC-MS: 98.1% MS(EI): 242.

8-Methoxyoct-1-ene (3h)

Under inert atmosphere sodium hydride (20.60 g, 858 mmol, 2.2 equiv.)was suspended in dry THF (300 mL) and a solution of oct-7-en-1-ol (1)(50.00 g, 390 mmol) was added dropwise to the suspension over a20-minute period, then it was stirred at rt for 30 min. After completionof the salt formation, iodomethane (66.4 g, 468 mmol, 1.2 equivalent)was added to the reaction mixture and it was stirred at rt overnight.After completion of the reaction the reaction mixture was concentratedto ⅓ and the residue was dissolved in chloroform (500 mL). The organicphase was washed with water (3×100 mL) and brine (2×100 mL), dried overmagnesium sulphate and evaporated. The crude product was purified bydistillation (65-70° C./25 Hg mm) to yield 26.50 g (47.80%) methyl ether(3h) as a colorless liquid. ¹H-NMR (200 MHz, CDCl₃): δ 1.24-1.44 (m,6H), 1.46-1.60 (m, 2H), 2.04 (q, J=7.0 Hz, 2H), 3.28 (s, 3H), 3.45 (t,J=7.0 Hz, 2H), 4.90-5.08 (m, 2H), 5.70-5.90 (m, 1H). GC-MS: 96.3% MS(EI): 142.

8-(tert-Butoxy)oct-1-ene (3i)

Ca. 3.0 equiv. of isobutylene was bubbled into the solution ofoct-7-en-1-ol (1) (150.0 g, 176.0 mL, 1170 mmol) and 0.2 equiv. ofsulphuric acid (23.90 g, 13.0 mL) in tert-butyl methyl ether (400 mL) at−20-−10° C. (ca. 25-35 min), then it was allowed to warm up to roomtemperature and stirred for 24 h. After completion of the reaction (TLC:Hep:EtOAc=7:3) the excess of isobutylene was removed in vacuum (500Hgmm), then the reaction mixture was diluted with sat. Na₂CO₃ (the pHwas adjusted to 7.5-8.5), the phases were separated, the aqueous phasewas extracted with tert-butyl methyl ether (2×150 mL). Combined organicphases were washed with water (3×150 mL), brine (3×150 mL), dried overCaCl₂ (min. 8-12 h) and evaporated. The crude product was purified byvacuum distillation (69-74° C./8 Hg mm) to yield 153.00 g (71.10%) 3i asa colorless liquid. ¹H-NMR (200 MHz, CDCl₃): δ 1.18 (s, 9H), 1.26-1.42(m, 6H), 1.44-1.58 (m, 2H), 2.03 (q, J=7.0 Hz, 2H), 3.32 (t, J=7.0 Hz,2H), 4.87-5.06 (m, 2H), 5.70-5.92 (m, 1H). GC-MS: 98.0% MS (EI): 184.

1-Ethoxy-1-(oct-7-en-1-yloxy)ethane (3j)

A catalytic amount of trifluoroacetic acid (0.178 g, 1.56 mmol, 0.005equivalent) was added to the solution of oct-7-en-1-ol (1) (40.00 g, 312mmol) and ethyl vinyl ether (10) (67.50 g, 936 mmol, 3.0 equivalent) at0-5° C., then the reaction mixture allowed to warm up to rt and stirredfor 2 h. After completion of the reaction, it was diluted with ether(500 mL) and washed with saturated aqueous solution of NaHCO₃ (3×100mL), water (2×100 mL) and brine (2×100 mL), dried over magnesiumsulphate and evaporated. The crude product was purified by distillation(82-84° C./6 Hg mm) to yield 36.54 g (58.50%) 3j as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 1.21-1.65 (m, 14H), 2.03 (q, J=7.0 Hz, 2H),3.35 (t, J=7.0 Hz, 2H), 3.61 (q, J=7.0 Hz, 3H), 4.71 (q, J=7.0 Hz, 1H),4.92-5.10 (m, 2H), 5.68-5.91 (m, 1H). GC-MS: 96.9% MS (EI): 200.

8-Bromooct-1-ene (3k)

Phosphorus tribromide (27.21 g, 97.5 mmol, 0.5 equiv.) was addeddropwise to a solution of oct-7-en-1-ol (1) (25.00 g, 195 mmol) in drydichloromethane (200 mL) at 0° C. After completion of the addition itwas allowed to warm up to rt and stirred for 2 h, then the reactionmixture was poured into saturated aqueous solution of NaHCO₃ to adjustthe pH to 7.0. Phases were separated and the organic phase was washedwith water (3×75 mL), brine (3×75 mL), dried over magnesium sulphate andevaporated. The crude product was purified by vacuum distillation(59-61° C./7 Hg mm) to yield 6.20 g (16.60%) 3k as a colorless liquid.¹H-NMR (200 MHz, CDCl₃): δ 1.20-1.50 (m, 6H), 1.76-1.92 (m, 2H),1.96-2.14 (m, 2H), 3.14 (t, J=7.0 Hz, 2H), 4.90-5.08 (m, 2H), 5.70-5.92(m, 1H). GC-MS: 96.8% MS (EI): 190, 192.

Methyl oct-7-enyl carbonate (3l)

Under inert atmosphere a 2.5M solution of butyllithium (93.6 mmol, 25.95g, 37.4 mL) was added dropwise to a solution of oct-7-en-1-ol (1) (10.00g, 78 mmol) in dry THF (100 mL) at 0° C. then it was stirred at the sametemperature for 30 min. After completion of the salt formation, methylchloroformate (8.85 g, 93.6 mmol, 7.23 mL) was added to the reactionmixture and it was stirred at rt overnight. After completion of thereaction the reaction mixture it was quenched with saturated aqueoussolution of ammonium chloride and it was extracted with dichloromethane(3×100 mL). The organic phase was washed with water (2×50 mL) and brine(50 mL), dried over magnesium sulphate and evaporated. The crude productwas purified by distillation (105-107° C./20 Hgmm) to yield 7.72 g(53.10%) carbonate (3l) as a colorless liquid. ¹H-NMR (300 MHz, CDCl₃):δ 1.21-1.48 (m, 6H), 1.55-1.70 (m, 2H), 1.95-2.05 (m, 2H), 3.78 (s, 3H),3.88 (t, J=7.1 Hz, 2H), 4.90-5.06 (m, 2H), 5.70-5.90 (m, 1H). GC-MS:97.2% MS (EI): 187.

Methyl dec-9-enoate (11a)

Decenoic acid (12) (32.60 g, 192 mmol) was dissolved in dry methanol(300 mL) and 0.1 equiv. of sulfuric acid (1.96 g, 1.07 mL, 19.2 mmol)was added to the reaction mixture and it was refluxed for 20 h. Aftercompletion of the reaction it was quenched with saturated aqueoussolution of NaHCO₃ (25 mL) and evaporated. The residue was dissolved inchloroform (300 mL) and washed with water (3×75 mL) and brine (2×75 mL),dried over magnesium sulphate and evaporated. The crude product waspurified by flash column chromatography (n-HeptaneEthyl acetate; 20:1)gave 25.50 g (72.30%) of the title compound (11a) as a colorless liquid.GC-MS: >98.1% MS (EI): 184.

Ethyl dec-9-enoate (11b)

Decenoic acid (12) (30.60 g, 180 mmol) was dissolved in dry methanol(300 mL) and 0.1 equivalent of sulfuric acid (1.84 g, 0.99 mL, 18 mmol)was added to the reaction mixture and it was refluxed for 20 h. Aftercompletion of the reaction it was quenched with saturated aqueoussolution of NaHCO₃ (25 mL) and evaporated. The residue was dissolved inchloroform (300 mL) and washed with water (3×75 mL) and brine (2×75 mL),dried over magnesium sulphate and evaporated. The crude product waspurified by flash column chromatography (n-HeptaneEthyl acetate; 20:1)to yield 23.50 g (65.90%) of the title compound (11b) as a colorlessliquid. GC-MS: >98.5% MS (EI): 198.

Propan-2-yl dec-9-enoate (11c)

Decenoic acid (12) (15.00 g, 88.1 mmol) was dissolved in dry 2-propanol(200 mL) and 0.1 equiv. of sulfuric acid (0.9 g, 0.49 mL, 8.81 mmol) wasadded to the reaction mixture and it was refluxed for 20 h. Aftercompletion of the reaction it was quenched with saturated aqueoussolution of NaHCO₃ (25 mL) and evaporated. The residue was dissolved inchloroform (300 mL) and washed with water (3×75 mL) and brine (2×75 mL),dried over magnesium sulphate and evaporated. The crude product waspurified by distillation (98-104° C./8 Hg mm) to yield 14.56 g (77.80%)of the title compound (11c) as a colorless liquid. GC-MS: >99.0% MS(EI): 212.

Cross Metathesis of Oct-7-Enol and 3-Methylhex-5-Enol Derivatives:

All metathesis reactions were carried out in a nitrogen-filled gloveboxin oven dried glassware.

General Procedure of Cross Metathesis Reactions withoutTrioctylalunninunn (Procedure A):

In an open screw cap vial the 0.1 M solution of metathesis catalyst (indry benzene) (25-1000 ppm) was added to the mixture of decenoate (11a-c)(10.9 mmol) and octenol derivative (3a-q and 13) (10.9 mmol) and thereaction mixture was stirred at rt for 4-20 h, then it was quenched with0.2 mL diethyl ether (Analysis: ca. 100 μL of the reaction mixture wasfiltered through a silica pad (ca. 4-5 mL) the pad was washed with amixture of n-heptane and EtOAc (7:3, 15 mL) and the filtrate wasanalyzed by GC-MS.).

General Procedure of Cross Metathesis Reactions in the Presence ofTrioctylaluminum (Procedure B):

In an open screw cap vial 0.5 mol % of trioctylaluminum was added to themixture of decenoate (11a-c) (10.9 mmol) and octenol derivative (3a-qand 13) (10.9 mmol) and the reaction mixture was stirred at rt for 1 h,then the 0.1 M solution of metathesis catalyst (in dry benzene) (25-1000ppm) was also added to the reaction mixture and stirring was continuedfor 4-20 h, then it was quenched with 0.2 mL diethyl ether (Analysis:ca. 100 μL of the reaction mixture was filtered through a silica pad(ca. 4-5 mL), the pad was washed with the mixture of n-heptane and EtOAc(7:3, 15 mL) and the filtrate was analyzed by GC-MS.).

EXAMPLE 1

In an open screw cap vial the 0.1 M solution of X052 in dry benzene(10.9 μL, 50 ppm) was added to the mixture of purified methyl decenoate(11a) (2.00 g, 10.9 mmol, 2.28 mL) and purified tert-butyl ether (3i)(2.00 g, 10.9 mmol, 2.52 mL) and the reaction mixture was stirred at rtfor 20 h, then it was quenched with 0.2 mL of diethyl ether (Analysis:ca. 100 μL of reaction mixture was filtered through silica pad (ca. 4-5mL) and washed with the mixture of n-heptane and EtOAc (7:3, 15 mL) andthe filtrate was analyzed by GC-MS.). The CM reaction of 11a with 3iafforded a statistical mixture of 14i, 16ai and 18a (1:2:1) with 95%conversion for both starting olefins and E/Z ratios were found to be85/15 for all three compounds.

EXAMPLE 2

In an open screw cap vial 0.5 mol % of trioctylaluminum (25 w % inhexane) (80 mg, 5.45*10⁻² mmol, 114 μL) was added to the mixture ofmethyl decenoate (11a) (2.00 g, 10.9 mmol, 2.28 mL) and tert-butyl ether(3i) (2.00 g, 10.9 mmol, 2.52 mL) and the reaction mixture was stirredat rt for 1 h, then the 0.1 M solution of X190 in dry benzene (5.45 μL,25 ppm) was also added to the reaction mixture and stirring wascontinued for 20 h, then it was quenched with 0.2 mL of diethyl ether(Analysis: ca. 100 μL of the reaction mixture was filtered throughsilica pad (ca. 4-5 mL) and washed with the mixture of n-heptane andEtOAc (7:3, 15 mL) and the filtrate was analyzed by GC-MS.). The CMreaction of 11a with 3i afforded a statistical mixture of 14i, 16ai and18a (1:2:1) with 95% conversion for both starting olefins and E/Z ratioswere found to be 84/16 for all three compounds.

EXAMPLE 3

Methyl decenoate (11a) (51.2 g, 278 mmol, 58.0 mL) and tert-butyloctenyl ether (3i) (50.4 g, 273 mmol, 63.0 mL) were charged in a 500 mLround-bottom flask and the mixture was stirred for ten minutes, then 0.1M solution of X039 in dry benzene (560 μL, 100 ppm) was added in oneportion. The reaction vessel was connected to a vacuum pump and thereaction mixture was stirred at room temperature under 50 mbar dynamicvacuum for 4 hours. GC-MS analysis of the crude product found 90%conversion for both starting olefins. Non-anhydrous ethyl acetate (10mL) was added to the reaction mixture to quench the metathesis reaction.The quenched mixture was passed through a pad of silica (approx. 20 mL)using 500 mL ethyl acetate as eluent. Volatiles were removed in vacuo toafford the crude product as a practically colourless oil (92.4 g).Metathesis products 14i, 16ai and 18a were formed in the statistical(1:2:1) ratio and E/Z ratios were found to be 9/91 for all threecompounds.

EXAMPLE 4

Methyl decenoate (11a) (0.675 g, 3.66 mmol, 765 μL) and octenyl acetate(3m) (0.623 g, 3.66 mmol, 700 μL) were charged in a 30 mL glass vial andthe mixture was homogenized, then 0.1 M solution of X054 in dry benzene(74 μL, 1000 ppm) was added in one portion. The vial was connected to avacuum pump and the reaction mixture was stirred under 50 mbar dynamicvacuum at room temperature for 6 hours (90% conversion for both startingolefins according to GC-MS). Non-anhydrous diethyl ether (10 mL) wasadded to it to quench the metathesis reaction. The mixture was passedthrough a silica pad (10 mL) using n-HeptaneEthyl acetate; 1:1 solventmixture as eluent. Approximately 75 mL filtrate was collected. Solventwas removed in vacuo to afford the metathesis product mixture as aslightly brownish oil (1.18 g). Metathesis products 14m, 16am and 18awere formed in the statistical (1:2:1) ratio and E/Z ratios were foundto be 11/89 for all three compounds.

EXAMPLE 5

Methyl decenoate (11a) (21.4 mg, 0.116 mmol, 24.2 μL) and octenylacetate (3m) (19.6 mg, 0.115 mmol, 22.0 μL) were charged in a 4 mL glassvial and the mixture was homogenized, then 0.1 M solution of X038 in drybenzene (11.5 μL, 5000 ppm) was added in one portion. The vial wasclosed with a pierced cap and the reaction mixture was stirred underatmospheric pressure at room temperature. (Analysis: 20 μL of thereaction mixture was mixed with 200 μL of non-anhydrous diethyl etherwithin the glovebox to quench the metathesis reaction, then the quenchedsample was passed through a silica plug (approx. 2 cm thick layer in aPasteur-pipette) using 4 mL n-HeptaneEthyl acetate; 1:1 solvent mixtureas eluent and the filtrate was analyzed by GC-MS. Sample taken after 2hours showed 57% conversion for both starting olefins (11a, 3m) andcross metathesis products 14m, 16am and 18a were formed in thestatistical (1:2:1) ratio. E/Z ratios were found to equal to 3/97 forall three cross metathesis products. A sample was taken after 2.5 daysto find only 68% conversion of both starting olefins and E/Z=4/96 ratiosfor all three metathesis products.

EXAMPLE 6

In an open screw cap vial the 0.1 M solution of X190 in dry benzene(26.2 μL, 400 ppm) was added to the mixture of purified methyl decenoate(11a) (600 mg, 3.27 mmol, 683 μL) and purified carbonate (3l) (609 mg,3.27 mmol) and the reaction mixture was stirred at rt for 20 h, then itwas quenched with 0.2 mL of diethyl ether (Analysis: ca. 100 μL ofreaction mixture was dissolved in methanol (1 mL) and a small amountsodium methoxide was added to the solution and it was stirred at rt for4 h. After that it was diluted with water (0.5 mL) and extracted withdichloromethane (2×2 mL), dried over magnesium sulphate and evaporated.The sample was analyzed by GC-MS.). The CM reaction of 11a with 3lafforded a statistical mixture of 14l, 16al and 18a (1:2:1) with 95%conversion.

EXAMPLE 7

In an open screw cap vial 0.5 mol % of trioctylaluminum (25 w % inhexane) (40 mg, 2.72*10⁻² mmol, 57 μL) was added to the mixture ofmethyl decenoate (11a) (1.00 g, 5.43 mmol, 1.13 mL) and carbonate (3l)(1.00 g, 5.43 mmol) and the reaction mixture was stirred at rt for 1 h,then the 0.1 M solution of X190 in dry benzene (21.7 μL, 200 ppm) wasalso added to the reaction mixture and stirring was continued for 20 h,then it was quenched with 0.2 mL of diethyl ether (Analysis: ca. 100 μLof reaction mixture was dissolved in methanol (1 mL) and a small amountsodium methoxide was added to the solution and it was stirred at rt for4 h. After that it was diluted with water (0.5 mL) and extracted withdichloromethane (2×2 mL), dried over magnesium sulphate and evaporated.The sample was analyzed by GC-MS.). The CM reaction of 11a with 3lafforded a statistical mixture of 14l, 16al and 18a (1:2:1) with 35%conversion.

EXAMPLE 8

Methyl decenoate (11a) (0.098 g, 0.50 mmol, 104 μL) and3-methylhex-5-enyl acetate (13) (0.078 g, 0.50 mmol, 85 μL) weremeasured into a 4 mL vial, 0.1 M solution of X054 in dry benzene (5.0μL, 500 ppm) was added in one portion, then the vial was connected to avacuum pump and the reaction was stirred at room temperature under 50mbar dynamic vacuum (Analysis: 5.0 μL of the reaction mixture was mixedwith 200 μL non-anhydrous diethyl ether to quench the metathesisreaction, then the quenched sample was passed through a silica plug(approx. 2 cm thick layer in a Pasteur-pipette) using 4 mL n-HeptaneEthyl acetate; 1:1 solvent and the filtrate was analyzed by GC-MS.Sample taken after 19 hours showed 97% conversion for both startingolefins (11a, 13) and cross metathesis products 15, 17 and 18a wereformed in the statistical (1:2:1) ratio. Since E- and Z-isomers of theacetate compound 17 separate less readily in GC-MS than isomers ofdeprotected alcohol 22, the acetate moiety was selectively cleaved viatrans-esterification of 20 μL reaction mixture samples with drymethanol/NaOMe (1.0 mL methanol, approx. 5 mg NaOMe) following aprotocol analogous to that described in Example 9. The resultingmaterial was analyzed by GC-MS to determine E/Z ratio of compound 17. Itwas found that the more branched the chain is (2, 1 or no methyl groupsin homoallylic position(s) of the double bond, the higher theZ-selectivity is. E/Z ratios for cross metathesis products: 15 (2/98);17 (5/95); 18a (7/93). A sample taken only after 4 hours showed 89%conversion for 13 and 95% conversion 11a, indicating that the morebranched substrate undergoes metathesis less readily. E/Z ratios werethe same as those reported for the sample taken after 19 hours.

EXAMPLE 9

The experiment described in Example 8 was repeated using catalyst X039.In this case 96% conversion of both starting olefins was achieved within4 hours. Cross metathesis products 15, 17 and 18a were again formed inthe statistical (1:2:1) ratio. E/Z ratios: 15 (2/98); 17 (7/93); 18a(12/88).

EXAMPLE 10

Cleavage of a tBu-Ether Protecting Group

Crude product obtained in Example 3 was charged in a 500 mL two-neckedround-bottom flask and dissolved in dry dichloromethane (200 mL, freshlydistilled from CaH₂). The flask was flushed with nitrogen and cooled to0° C. by applying an ice/water bath. Titanium tetrachloride was added insmall portions over 15 minutes and the mixture was stirred foradditional 15 minutes. Still at 0° C., under constant cooling, saturatedaqueous solution of NH₄Cl solution (20 mL) was added dropwise. Themixture was allowed to warm to room temperature and brine was added toease phase separation (1×100 mL). Phases were separated and the organicphase was washed with brine (2×50 mL) and dried over MgSO4. Volatileswere removed in vacuo. Column chromatographic purification of theresulting oil using silica and n-heptanediethyl ether; 2:1 as eluentafforded the desired product (21a) as a colorless oil (31.0 g, 109 mmol,79% overall yield for the cross metathesis and tert-butyl cleavagesteps). The E/Z isomer ratio was invariably 9/91.

Synthesis of Ambrettolide Intermediate w-Hydroxy Esters (21a-c, 22) ViaSelective Alcohol Deprotection:

EXAMPLE 11

Cleavage of an Ester Protecting Group

The crude product obtained in Example 4 was dissolved in 3 mL drymethanol, 20 mg sodium methylate was added and the mixture was stirredat room temperature for 2 hours. The mixture was passed through a silicapad (7 mL silica) and the pad was washed with ethyl acetate (75 mL). Thefiltrate was evaporated to afford 1013 mg crude transesterificationproduct. The desired product was isolated by flash column chromatographyusing n-heptanediethyl ether; 2:1. The desired product (21a, R₁=Me) wasobtained as a yellowish oil (355 mg, 1.25 mmol, 68% overall yield forthe cross metathesis and acetate cleavages). The E/Z isomer ratio wasinvariably 11/89.

GC-MS Analytical Method for Product Identification (Method A):

GC analyses were run using a flame ionization detector (FID). Column:ZB-35HT Inferno (35% Phenyl 65% Dimethylpolysiloxane) from Phenomenex;30 m×0.25 mm (i.d.)×0.25 mm film thickness. GC and column conditions:injector temperature 370° C.; detector temperature 240° C.; oventemperature, starting temperature 50° C., hold time 5 min, ramp rate 25°C./min to 340° C., hold time 12 min; carrier gas nitrogen.

GC-MS Analytical Method for Product Identification (Method B):

GC analyses were run using a flame ionization detector (FID). Column:ZB-35HT Inferno (35% Phenyl 65% Dimethylpolysiloxane) from Phenomenex;30 m×0.25 mm (i.d.)×0.25 mm film thickness. GC and column conditions:injector temperature 370° C.; detector temperature 240° C.; oventemperature, starting temperature 55° C., hold time 2 min, ramp rate 25°C./min to 200° C., hold time 0 min; ramp rate 4° C./min to 260° C., holdtime 0 min, ramp rate 40° C./min to 340° C., hold time 3.2 min carriergas nitrogen.

TABLE 1 Cross metathesis of decenoic acid esters and protectedoct-7-enol derivatives. Cat- Loading Con- E/Z Entry Substrates alyst(ppm (mol)) version ratio Procedure  1 11a and 3m X007 2000 ppm 80%82/18 A  2 11a and 3m X007 1000 ppm 15% 80/20 A  3 11a and 3m X008 2000ppm 25% 81/19 A  4 11a and 3m X001 2500 ppm 85% 85/15 A  5 11a and 3mX030 2000 ppm 50% 83/17 A  6 11a and 3m X041 2000 ppm 50% 83/17 A  7 11aand 3m X042 2000 ppm 90% 84/16 A  8 11a and 3m X046 2000 ppm 90% 81/19 A 9 11a and 3m X040 2000 ppm 95% 85/15 A 10 11a and 3m X042 1000 ppm 80%83/17 A 11 11a and 3m X052 1000 ppm 85% 84/16 A 12 11a and 3m X051 1000ppm 35% 85/15 A 13 11a and 3m X004 1000 ppm 60% 86/14 A 14 11a and 3mX042  500 ppm 15% 85/15 A 15 11a and 3m X123  200 ppm 10% 85/15 B 16 11aand 3m X054 1000 ppm 90% 11/89 Example 4 17 11a and 3m X038 5000 ppm 68% 4/96 Example 5 18 11a and 3h X042 1000 ppm 95% 84/16 A 19 11a and 3hX052 1000 ppm 95% 85/15 A 20 11a and 3h X052  250 ppm 95% 84/16 A 21 11aand 3h X042  250 ppm 95% 85/15 A 22 11a and 3h X052  100 ppm 95% 84/16 A23 11a and 3h X042  100 ppm 95% 85/15 A 24 11a and 3h X052  50 ppm 85%85/15 A 25 11a and 3h X042  50 ppm 40% 84/16 A 26 11a and 3h X051  50ppm 75% 85/15 A 27 11a and 3h X061  50 ppm 85% 84/16 A 28 11a and 3hX062  50 ppm 65% 84/16 A 29 11a and 3h X063  50 ppm 40% 70/30 A 30 11aand 3g X052  100 ppm 95% 84/16 A 31 11a and 3g X042  100 ppm 70% 85/15 A32 11a and 3i X052  100 ppm 90% 83/17 A 33 11b and 3i X052  100 ppm 95%85/15 A 34 11c and 3i X052  100 ppm 95% 84/16 A 35 11a and 3i X039  100ppm 90%  9/91 Example 3 36 11a and 3i X052  50 ppm 90% 84/16 A 37 11aand 3i X061  50 ppm 20% 83/17 A 38 11a and 3i X059  50 ppm 20% 84/16 A39 11a and 3i X004  50 ppm 20% 85/15 A 40 11a and 3i X076  50 ppm 90%60/40 A 41 11a and 3i X114  50 ppm 15% 80/20 A 42 11a and 3i X123  50ppm 85% 85/15 A 43 11a and 3i X123  25 ppm 90% 85/15 B 44 11a and 3iX149  25 ppm 10% 84/16 B 45 11a and 3i X154  25 ppm 85% 85/16 B 46 11aand 3i X123  17 ppm 75% 84/16 B 47 11a and 3i X123  12 ppm 55% 84/16 B48 11a and 3l X190 400 95% n/a Example 6 49 11a and 3l X190 200 32% n/aA 50 11a and 3l X190 200 35% n/a Example 7 51 11a and 3l X190 100 10%n/a A

TABLE 2 Cross metathesis of decenoic acid esters and protectedoct-7-enol derivatives. Loading Con- E/Z Entry Substrates Catalyst (ppm(mol)) version ratio Procedure 48 11a and 3i X190  25 ppm 85% 85/15 B 4911a and 3f X052  50 ppm 60% 84/16 B 50 11a and 3f X123  50 ppm 90% 85/15B 51 11a and 3f X123  25 ppm 80% 84/16 B 52 11a and 3o X123  50 ppm 50%84/16 B 53 11a and 3n X123  50 ppm 45% 85/15 B 54 11a and 3c X052 250ppm 50% 84/16 A 55 11a and 3c X123 250 ppm 80% 85/15 A 56 11a and 3dX052 500 ppm 90% 84/16 A 57 11a and 3d X123 500 ppm 90% 85/15 A

TABLE 3 Cross metathesis of methyl dec-9-enoate (11a) and3-methylhex-5-enyl acetate (13). Loading E/Z Entry Substrates Catalyst(ppm (mol)) Conversion ratio Procedure 1 11a and 13 X054 500 ppm 97% (19h) 5/95 Example 6 2 11a and 13 X039 500 ppm 96% (4 h)  7/93 Example 7

TABLE 4 Characterization of cross metathesis products. CM Entry productsGC-MS Retention MS (mw)  1 16aa Method A 15.82 min 368 [M]⁺  2 16abMethod A 16.44 min 368 [M]⁺  3 16ac Method A 16.74 min 382 [M]⁺  4 16adMethod A 17.10 min 396 [M]⁺  5 16ae Method A 18.25 min 438 [M]⁺  6 16afMethod A 15.02 min 356 [M]⁺  7 16ag Method A 15.72 min 399 [M]⁺  8 16ahMethod A 14.60 min 298[M]⁺  9 16ai Method A 15.31 min 284 [M − CCH₃]⁺ 1016aj Method A 15.52 min 355 [M]⁺ 11 16ak Method A 15.98 min 346, 348[M]⁺  12^(a) 16al Method A 14.98 min 284 [M]⁺ 13 16an Method A 15.43 min326 [M]⁺ 14 16ao Method A 15.83 min 340 [M]⁺ 15 16ap Method A 15.94 min354 [M]⁺ 16 16ar Method A 16.03 min 325 [M]⁺ 17 16bi Method A 15.27 min355 [M]⁺ 18 16bj Method A 15.72 min 298 [M − CH(CH₃)OC₂H₅]⁺ 19 16bnMethod A 15.68 min 340 [M]⁺ 20 16ci Method A 15.30 min 312 [M − CCH₃]⁺21 16cj Method A 15.75 min 385 [M]⁺ 22 17 Method B 15.74 min 312 [M]⁺,252 [M − AcOH]⁺ ^(a)Before the product identification the protectivegroup was cleaved by sodium methoxide in methanol.

Recycling of Homodimeric Side Product(s) Via Cross Metathesis:

EXAMPLE 12

(Scenario 1):

The homodimer of tert-butyl octenyl ether (14i) (0.085 g, 0.25 mmol, 100μL, E/Z=85/15) and the homodimer of methyl dec-9-enoate (18a) (0.086 g,0.25 mmol, 92 μL, E/Z=85/15) were charged in a 4 mL screw cap vial andthe mixture was homogenized. Metathesis catalyst X190, (1.0*10⁻⁴ mmol,10 μL, 0.01 M in benzene) was added in one portion. The vial was closedwith a septum cap and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was subjected to air andmixed with 1 mL non-anhydrous ethyl acetate to quench the reaction. Thesample was then passed through a silica pad using pure ethyl acetate aseluent (5 mL) and the filtrate was analyzed by GC-MS. The reactionafforded 14i, 16ai and 18a with 95% recycling efficiency. In case ofcompound 16ai the ratio of E- and Z-isomers was found to correspond tothe thermodynamical equilibrium value (E/Z=85/15).

EXAMPLE 13

(Scenario 2):

8-(tert-Butoxy)oct-1-ene (3i) (0.092 g, 0.50 mmol, 114 μL) and methyldec-9-enoate (11a) (0.092 g, 0.50 mmol, 104 μL) along with the homodimerof tert-butyl octenyl ether (14i) (0.086 g, 0.25 mmol, 100 μL,E/Z=85/15) and the homodimer of methyl dec-9-enoate (18a) (0.086 g, 0.25mmol, 92 μL, E/Z=85/15) were charged in a 4 mL screw cap vial and themixture was homogenized. Metathesis catalyst X052 (2.0*10⁻⁴ mmol, 20 μL,0.01 M in benzene) was added in one portion. The vial was closed with apierced cap and the reaction mixture was stirred at room temperature.Samples (10 μL) taken from the reaction mixture after 2 h and 18 hreaction times were subjected to air and mixed with 0.2 mL non-anhydrousdiethyl ether to quench the reaction. The samples were then passedthrough a silica pad using pure EtOAc as eluent (5 mL) and the filtratewas analyzed by GC-MS. For the sample taken at 2 hours reaction timeGC-MS analysis found 90% recycling efficiency and in case of compound16ai the ratio of E- and Z-isomers was found to correspond to thethermodynamical equilibrium value (E/Z=85/15). The sample taken after 18hours showed identical values regarding both recycling efficiency andE/Z ratio.

EXAMPLE 14

(Scenario 3):

Methyl dec-9-enoate (11a) (0.184 g, 1.0 mmol, 208 μL) and the homodimerof tert-butyl octenyl ether (14i) (0.170 g, 0.5 mmol, 200 μL, E/Z=85/15)were charged in a 4 mL screw cap vial along with trioctylaluminum(4.0*10⁻⁴ mmol, 16.8 μL, 0.024 M in benzene) and the mixture was stirredat room temperature for 3.5 hours, then metathesis catalyst X190(4.0*10⁻⁴ mmol, 40 μL, 0.01 M in benzene) was added in one portion. Thevial was closed tightly and the reaction mixture was stirred at roomtemperature for 1.5 hours. The vial was connected to a 50 mbar dynamicvacuum source and its content was stirred for further 2.5 hours. Thereaction mixture was subjected to air and mixed with 1 mL non-anhydrousethyl acetate to quench the reaction. The sample was then passed througha silica pad using pure ethyl acetate as eluent (5 mL) and the filtratewas analyzed by GC-MS. GC-MS analysis found 95% recycling efficiency andin case of compound 16ai the ratio of E- and Z-isomers was found tocorrespond to the thermodynamical equilibrium value (E/Z=85/15).

EXAMPLE 15

(Scenario 4):

8-(tert-Butoxy)oct-1-ene (3i) (0.186 g, 1.0 mmol, 235 μL) and thehomodimeric olefin (18a) (0.170 g, 0.5 mmol, 183 μL, E/Z=85/15) werecharged in a 4 mL screw cap vial along with trioctylaluminum (2.0*10⁻⁴mmol, 8.4 μL, 0.024 M in benzene) and the mixture was stirred at ca. 30°C. for 3.5 hours, then metathesis catalyst X190 (2.0*10⁻⁴ mmol, 20 μL,0.01 M in benzene) was added in one portion. The vial was closed tightlyand the reaction mixture was stirred at ca. 30° C. for 1.0 hours. Thevial was connected to a 50 mbar dynamic vacuum source and its contentwas stirred for further 1.5 hours. The reaction mixture was subjected toair and mixed with 1 mL non-anhydrous ethyl acetate to quench thereaction. The sample was then passed through a silica pad using pureethyl acetate as eluent (5 mL) and the filtrate was analyzed by GC-MS.GC-MS analysis found 95% recycling efficiency and in case of compound16ai the ratio of E- and Z-isomers was found to correspond to thethermodynamical equilibrium value (E/Z=85/15).

TABLE 5 Selected examples of recycling experiments based on variousstrategies outlined in Scheme Substrates, Loading (ppm (mol)) Recyclingmolar in monomer efficiency E/Z ratio Entry ratios Catalystequivalents^(a) %^(b) (16ai) Procedure 1 14i, 18a X190 100 ppm 95% 85/15Example 10 2 1:1 X052 100 ppm 40% 85/15 Conditions of Example 10 3 3i,11a, 14i, X052 100 ppm 90% 85/15 Example 11 4 18a X190 100 ppm 70% 85/15Conditions of 2:2:1:1 Example 11 5 11a, 14i X190 200 ppm 95% 85/15Example 12 2:1 6 3i, 18a X190 100 ppm 95% 85/15 Example 13 2:1^(a)Monomeric olefins (3i, 11a) equal to 1, while homodimeric olefins(14i, 18a) equal to 2 equivalents of monomeric units. Loadings are givenwith respect to the sum of all olefinic starting materials.^(b)Recycling efficiency is calculated in the following way: rec.efficiency % = [n(octenyl units in 16ai/Σn(octenyl units in any form) +n(octenyl units in 16ai/Σn(octenyl units in any form)]*100. Its value is0% for all starting mixtures and equals to 100% for a statisticalmixture of 14i, 16ai, 18a.

Experimental Details on the Recycling of Homodimeric Side Product(s) ViaEthenolysis:

TABLE 6 Ethenolysis of tert-butyl ether dimer (14i).^(a) Entry SubstrateCatalyst Loading (ppm (mol)) Conversion 1 14i X041 400 ppm 65% 2 14iX042 400 ppm 60% 3 14i X052 400 ppm 75% 4 14i X076 400 ppm 60% 5 14iX041 200 ppm 57% 6 14i X042 200 ppm 41% 7 14i X052 200 ppm 52% 8 14iX076 200 ppm 33%  9^(b) 14i X041 200 ppm 91% 10^(b)   14i X052 200 ppm62% ^(a)All reactions were carried out at 0.73 mmol scale, reactionmixtures were stirred at room temperature for 16 h under 11.5 barethylene pressure. ^(b)n-Heptane was used as solvent to increase thesolubility of ethylene.

EXAMPLE 16

General Procedure of Ethenolysis (for Results in Table 6.):

In an open screw cap vial the 0.1 M solution of metathesis catalyst (indry benzene) (200-400 ppm) was added to 14i or 18a (0.73 mmol) and thereaction mixture was stirred at rt under 11.5 bar ethylene for 20 h,then it was quenched with 0.2 mL diethyl ether (Analysis: ca. 100 μL ofthe reaction mixture was filtered through a silica pad (ca. 4-5 mL) thepad was washed with a mixture of n-heptane and EtOAc (7:3, 15 mL) andthe filtrate was analyzed by GC-MS.).

TABLE 7 Results of ethenolysis experiments. Loading Conversion EntrySubstrate Catalyst (ppm (mol))^(a) Conditions %^(b) 1 14i X061 1000 ppmExample 16 80% (isolated) 2^(c) X008 400 ppm 4x volume of 80% 3^(c) 200ppm pentane, r.t., 50% 11.5 bar, 12 h 4 18a X008 1000 ppm  Example 1786% (isolated) 5^(c) 400 ppm 4x volume of 50% pentane, r.t., 11.5 bar,12 h 6^(c) 400 ppm 4x volume of 55% 7^(c) 200 ppm pentane, 2.5 30% mol %Et₃Al, r.t. 1.5 h then catalyst X008, r.t., 11.5 bar, 12 h ^(a)Catalystloadings given with respect to starting homodimers (14i and 18a). ^(b)GCconversions unless indicated otherwise. ^(c)Reactions were carried outon 0.5 mmol scale. Work-up analogous to that described for experimentslisted in Table 6.

EXAMPLE 17

Diether (14i) (2.47 g; 7.25 mmol) was dissolved in 12.0 mL pentane in a30 mL oven-dried glass vial equipped with a stir bar, stock solution ofcatalyst X061 (0.1 M in benzene; 72.6 μL; 0.1 mol %) was added to thereaction mixture and the vial was placed into an autoclave (250 mL innervolume). The autoclave was closed and pressurized to 11.5 bar for 30minutes. Ethylene source was disconnected and the autoclave waschambered out from the glovebox. The reaction mixture was allowed tostir at room temperature for 12 hours. Ethylene was carefully released,the autoclave lid was removed and 1 mL heptane:EtOAc (non-anhydroussolvents) 1:1 solvent mixture was added subsequently to quench thereaction. The quenched reaction mixture was passed through a silica plug(ca. 10 cm silica layer in a 20 mL syringe barrel) using 150 mLheptane:EtOAc 1:1 solvent mixture as eluent. The filtrate wasconcentrated in vacuo and the oily residue was distilled bulb-to-bulb(3.0-3.3×10⁻² mbar; 52-55° C.) to afford recovered tert-butyl octenylether (3i) as a colorless oil (2.13 g; 11.56 mmol; yield: 80%).

EXAMPLE 18

Procedure and workup were identical to those describe in Example A butcatalyst X008 was used. Diester (18a) (2.27 g; 6.67 mmol) dissolved in9.6 mL n-pentane was ethenolyzed in the presence of catalyst X008 (0.1 Min benzene; 66.4 μL; 0.1 mol %). Bulb-to-bulb distillation (8.5-9.0×10⁻²mbar; 60-61° C.) afforded the title compound as a colorless oil (2.10 g;11.40 mmol; yield: 86%).

¹H-NMR analysis of the crude products before bulb-to-bulb distillationboth for Example 16 and Example 17 showed that crude products consistedof ca. 95% monomer (3i; 11a) and residues of unreacted homodimer (14i;18a). No signs of undesired side reactions during the ethenolysis orworkup were observed. NMR spectra of bulb-to-bulb distilled materialscorrespond to those of pure 3i and 11a.

1. A method of forming a macrocyclic musk compound comprising the stepsof: — i) cross-metathesizing a first olefin and a second olefin in thepresence of a homogeneous transition metal catalyst comprising analkylidene ligand, to form a statistical mixture of a hetero-dimerintermediate of said first and second terminal olefin, and homo-dimersii) separating the hetero-dimer from the statistical mixture of hetero-and homo-dimers iii) and cyclizing the hetero-dimer intermediate to formthe macrocyclic musk compound.
 2. A method according to claim 1 whereinthe first olefin has the formula (I)

wherein OR₂ is a protected hydroxyl group, which is selected from: analkyl ether group; an ester group; a silyl ether group; and a carbonategroup; R₃ is H or methyl; and, n is an integer from 1-8
 3. A methodaccording to claim 1, wherein the second olefin has the formula

wherein: R₇ is branched or non-branched alkyl moiety containing 1 to 5carbon atoms, and m is an integer from 1 to
 10. 4. A method according toclaim 1, wherein the hetero-dimer has the formula


5. A method according to claim 1, wherein the hetero-dimer has theformula


6. A method according to claim 1, wherein the hetero-dimer has theformula


7. A method according to claim 1, wherein the first olefin and secondolefin are reacted in a 1:x molar ratio to produce a ratio ofhetero-dimer:first homo-dimer:second homo-dimer of 2x:1:1x².
 8. A methodaccording to claim 1, wherein the hetero-dimer is formed in admixturewith a protected alcohol homo-dimer and a carboxylic acid esterhomo-dimer.
 9. A method according to claim 8 wherein the mixture ofprotected alcohol hetero-dimer and each carboxylic acid ester homo-dimeris formed in a molar ratio of 2:1:1.
 10. A method according to claim 1,wherein the hetero-dimer is separated from the homo-dimers bydistillation at a temperature of 100 to 220 degrees centigrade and apressure of 1 to 10 mbar.
 11. A method according to claim 1, wherein thehomo-dimers are recycled by metathesis with ethylene to regenerate thefirst and second olefins.
 12. A method according to claim 11 wherein thehomo-dimers are treated with ethylene gas at a pressure of 1 bar to 20bar.
 13. A method according to claim 1, wherein the hetero-dimer iscyclised by trans-esterification.
 14. A method according to claim 13wherein, if the hetero-dimer contains a protected alcohol group, it isfirst de-protected by hydrolysis before being subjected to cyclisationby tran-esterification.
 15. A method of forming E/Z 9-ambrettolideaccording to the method according to claim
 1. 16. A method of formingE/Z 9-ambrettolide according to claim 15, wherein the E/Z ratio is from80.20 to 90:10.
 17. A method according to claim 16 wherein the E/Z ratiois 85:15.
 18. A method according to claim 1, wherein the catalyst is amolybdenum or tungsten catalyst containing an alkylidene ligand.
 19. Amethod according to claim 1, wherein the catalyst is a compoundaccording to the formula:

wherein M=Mo or W; R¹ is aryl, heteroaryl, alkyl, or heteroalkyl; whichmay be substituted; R² and R³ can be the same or different and each ishydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, orheteroaryl; which may be substituted; R⁵ is alkyl, alkoxy, heteroalkyl,aryl, aryloxy, heteroaryl, silylalkyl, silyloxy, which may besubstituted; and R⁴ is a residue R⁶—X—, wherein X═O and R⁶ is aryl,which may be substituted; or X═S and R⁶ is aryl, which may besubstituted; or X═O and R⁶ is (R⁷, R⁸, R⁹)Si; wherein R⁷, R⁸, R⁹ arealkyl or phenyl, which may be substituted; or X═O and R⁶ is (R¹⁰, R¹¹,R¹²)C, wherein R¹⁰, R¹¹, R¹² are independently selected from phenyl,alkyl; which may be substituted; or, R⁴ and R⁵ are linked together andare bound to M via oxygen.
 20. E/Z 9-ambrettolide formed according to amethod according to claim
 1. 21. The hetero-dimer of the formula:

wherein: OR₂ is a protected hydroxyl group, selected from: an alkylether group; an ester group; a silyl ether group; or a carbonate group;R₃ is H or methyl; n is an integer from 1-8; and, R⁷ is a branched ornon-branched alkyl moiety containing 1 to 5 carbon atoms
 22. Thehetero-dimer according to claim 21 having the formula:


23. The hetero-dimer according to claim 21 or claim 22 having theformula:


24. E/Z Nirvanolide formed according to a method according to claim 1.25. The hetero-dimer according to claim 21 having the formula:


26. The hetero-dimer according to claim 25 having the formula:


27. A method according to claim 3, wherein: R₇ is methyl or ethyl.
 28. Amethod according to claim 3, wherein: m is 7.